SPINAL-CORD INJURY IN THE RAT - TREATMENT WITH BACTERIAL LIPOPOLYSACCHARIDE AND INDOMETHACIN ENHANCES CELLULAR REPAIR AND LOCOMOTOR FUNCTION

Trauma to the rat's spinal cord results in a lesion characterized by i ngrowth of glial cells, accumulation of macrophages, and the progressi ve development of necrosis and cavitation. Since, when appropriately a ctivated, both astrocytes and macrophages secrete growth-promoting cyt okines, we examined whether treatment with drugs that stimulate the se cretory activities of these cells might promote tissue repair and redu ce necrosis in the traumatized spinal cord. The spinal cord of rats wa s crushed extradurally at TS and the rats were injected intraperitonea lly with (i) a lipopolysaccharide (LPS) or ImuVert to activate cytokin e secretion, (ii) Indomethacin to reduce necrosis by inhibiting prosta glandin synthesis, (iii) a combination of LPS+Indomethacin, or (iv) ve hicle. After 28 days the lesion site was examined quantitatively by li ght microscopical image analysis. The lesion of vehicle-treated contro l animals showed large cavities, extensive infiltration by debris-engo rged macrophages, and relatively few axons. Treatment with LPS or ImuV ert significantly reduced the degree of cavitation and increased the n umber of cells and axons in the lesion. Treatment with LPS+Indomethaci n was significantly more effective than treatment with LPS alone, whil e treatment with Indomethacin alone was ineffective. To test whether t he histopathological differences between treated and control rats migh t be reflected in functional improvement, rats were subjected to a con tusion (weight-drop) injury and their walking ability was quantified b y the Tarlov scale for 28 days postoperatively. Treatment with LPS+Ind omethacin significantly improved locomotor function of animals subject ed to a moderate (1.25 g x 20 cm) injury. We conclude that tissue repa ir and functional recovery after spinal cord injury are enhanced by co mbined treatment with agents that promote the secretory activities of the nonneuronal cells and that inhibit prostaglandin synthesis. These results indicate that the search for more effective treatments should include studies on combinations of drugs having different pharmacologi cal specificities. (C) 1994 Academic Press, Inc.